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Home , Diastrophic dysplasia, Hypochondrogenesis, Metaphyseal dysplasia, Stickler syndrome, Thanatophoric dysplasia

Arch Dis Child 1998;79:285–289 285 Arch Dis Child: first published as 10.1136/adc.79.3.285 on 1 September 1998. Downloaded from PERSONAL PRACTICE

Skeletal dysplasias

C G D Brook, BBAdeVries

Making a diagnosis of a skeletal dysplasia on Table 1 Indications for performing a radiographic skeletal clinical grounds may be extremely easy but it survey maybesodiYcult that it is easy to miss. Table Disproportionate body segments for age and stage of puberty 1 shows the features that should alert the clini- Child with height prediction inappropriately short for the cian to request a radiographic skeletal survey— family, especially if growing at a normal rate the sine qua non of diagnosis. Failure to Unexpectedly poor response to usual doses of growth promoting agents (that is, resistance to a standard dose of diagnose mild cases of the more common skel- growth hormone) etal dysplasias leads clinicians to reassure Absent puberty growth spurt patients incorrectly about their future growth Short child with one (or more) very short parent, especially one with body disproportion prospects because usual prediction methods Otherwise unexplained short stature are not valid. Figure 1 shows the growth chart of such a patient. an inadequate puberty growth spurt in the legs, and skeletal radiography showed features char- Case report acteristic of . A male patient was seen in hospital for advice about short stature at the age of 5.7 years. An Clinical suspicion adopted child, previous measurements sug- Some skeletal dysplasias are so severe that they gested that he had grown at a normal rate since are detected by ultrasound before birth. Most the end of the first year of life and his short severe skeletal dysplasias, especially achondro- stature with delayed age was attributed to plasia and conditions resembling achondro- a failure of the infantile curve of growth. Follow plasia, are easily seen in neonates. There may up showed evidence of a mid-childhood growth well be disproportion between crown–rump spurt and the start of pubertal growth around and overall lengths, and associated features, http://adc.bmj.com/ 11 years. He was discharged just before his such as a large head and characteristic facies, 13th birthday as all appeared to be well but he will reinforce the clinical impression. The was referred again at 14.5 years because he had interpretation of skeletal radiographs at this age not grown as predicted. Measurement revealed is not easy and, because the categorisation of skeletal dysplasias is important to determine 190 97 outcome, caution should be exercised in oVer- 90 ing a firm diagnosis and prognosis in the first 180 75 50 year of life. A problem should be acknowledged on September 26, 2021 by guest. Protected copyright. 25 170 10 but a firm diagnosis postponed until skeletal 3 160 radiographic appearances in the early child- hood years are available. Advances in the 150 understanding of the molecular genetics of 140 skeletal dysplasia may assist in early, possibly prenatal, diagnosis. 130 During infancy and early childhood, growth London Centre for 120 disorders associated with the more severe cm Paediatric forms of skeletal dysplasia, such as achondro- Endocrinology, The 110 plasia and some forms of spondyloepiphyseal Middlesex Hospital, 100 dysplasia, become more obvious. To make a Mortimer Street, diagnosis, a radiological skeletal survey includ- London W1N 8AA, UK 90 C G D Brook ing the films shown in table 2 is required. The 80 measurement of body proportions may assist Department of Clinical 70 Genetics, University Table 2 Radiographs essential for making a diagnosis of Hospital Dijkzigt, 60 skeletal dysplasia Rotterdam, Netherlands 50 Postero-anterior and lateral chest BBAdeVries Antero-posterior abdomen to include pelvis 132 78645 9 10111213141516171819 Antero-posterior femora to include knees Age (years) Postero-anterior hands Correspondence to: Lateral skull Professor Brook. Figure 1 Growth chart of patient with missed diagnosis of Lateral lumbar spine email: [email protected] hypochondroplasia. 286 Brook, de Vries Arch Dis Child: first published as 10.1136/adc.79.3.285 on 1 September 1998. Downloaded from Table 3 Clinical and molecular characteristics of bone dysplasias

Gene/protein family Presenting at Major features Inherited Gene

Fibroblast 3 (FGFR3) Birth Short limbs AD FGFR3 low nasal bridge prominent forehead Hypochondroplasia Infancy/puberty Short limbs AD FGFR3 near normal face Birth (lethal) Very short limbs AD FGFR3 low nasal bridge prominent forehead narrow chest short/trident hands II/ Stillbirth/ neonatal Severe micromelia AD COL2A1 death short trunk/neck protuberant abdomen Spondyloepiphyseal dysplasia Birth/infancy Short trunk/lordosis AD COL2A1 congenita Kniest syndrome Birth Thick/stiV joints AD COL2A1 flat facies prominent eyes, myopia deafness, cleft palate Stickler dysplasia Childhood/adult Flat face AD COL2A1 severe myopia COL11A2 Pierre-Robin association Strudwick dysplasia Birth Short limbs AD COL2A1 severe pectus carinatum Multiple epiphyseal dysplasia Childhood/ Short stature AD COL9A2 adolescence painful/stiV joints COMP waddling gait

Schmid Childhood Short bowed limbs AD COL10A1 lumbar lordosis waddling gait oligomeric matrix protein (COMP) Multiple epiphyseal dysplasia (see under collagen) Birth/childhood Short limbs AD/AR COMP waddling gait lax joints normal face sulphate transporter (DTDST) Achondrogenesis IB Stillbirth/ neonatal Severe micromelia AR DTDST death low nasal bridge short neck/ protuberant abdomen

Atelosteogenesis II Neonatal death Severe micromelia AR DTDST http://adc.bmj.com/ short thorax bowed limbs/spine Diastrophic dysplasia Birth Rhizomelic shortening AR DTDST swelling of hitchhiker thumbs narrow thorax Parathyroid hormone, parathyroid hormone related peptide receptor (PTHrPR) Jansen metaphyseal dysplasia Birth/infancy Bowing long AD PTH-PTHrP narrow thorax flexion joint deformity on September 26, 2021 by guest. Protected copyright. prominent eyes/micrognathia

AD, autosomal dominant; AR, autosomal recessive. but not necessarily—for example, it is only reported to be the most common with an esti- during the (failure of the) puberty growth spurt mated frequency of 1/15 000–77 000 births,2 that short legs, characteristic of adults with but skeletal dysplasias with less severe pheno- lesser degrees of hypochondroplasia, become types (for example, the milder end of the spec- easily detectable. trum of hypochondroplasia) may go undiag- Reporting skeletal radiographs is not easy, nosed and be much more common. As and few radiologists see suYcient numbers of diagnosis has prognostic and genetic implica- such radiographs to give a reliable opinion. For tions, it is important that the clinician, geneti- some disorders it is possible to use molecular cist, and radiologist work closely together. genetic methods to confirm a suspected Before speaking to parents about their child’s diagnosis (table 3), but how best to investigate problem, it is sensible to insist on the this aspect without screening the genome radiologist, with whom team work has been depends on clinical acumen. Thus, recognition established, reporting on the x rays. In the case of clinical and radiological features is the best of achondroplasia, most clinicians and radiolo- that can be oVered, but as the patient shown in gists can probably agree a diagnosis and be fig 1 indicates, this is not easy. reasonably sure of the prognosis, but in the less common skeletal dysplasias not every radiolo- Diagnosis gist will classify the appearances identically and There are hundreds of skeletal dysplasias,1 there is scope for considerable confusion, espe- many of them very rare. Achondroplasia is cially if the radiologist qualifies opinion—“the Skeletal dysplasias 287 Arch Dis Child: first published as 10.1136/adc.79.3.285 on 1 September 1998. Downloaded from changes in the radiographs resemble disease receptor but this eVect is relatively weak in X”—and the clinician then addresses the achondroplasia , whereas the muta- parents as if the patient definitely has disease tions in thanatophoric dysplasia result in more X. powerful activation.7 When my radiologist puts a name to a The situation in hypochondroplasia, a more condition, regardless of whether his peers common disorder, is complicated. Severe cases would put the same name to it, it is known from with considerably short stature and obvious our experience together what is likely to disproportion have an asparagine→lysine sub- happen. In practical terms this means that, as stitution at codon 5408 but the cases that are in every field of medicine, team work pays oV easier to miss, such as the patient in fig 1, do and the referral of a child with their radio- not have this , even though the graphs to a specialist centre for diagnosis, if not skeletal radiographic findings are identical. We for management, is probably wise. do not yet understand the molecular genetic As the phenotypic appearances of the same basis of this disorder, and the spectrum of bone dysplasias can be extremely variable, dys- genotype and phenotype needs to be clarified morphic features, in addition to radiological urgently to know whom to treat and when. findings, may be very helpful in reaching a Collagen II is primarily expressed in carti- diagnosis. For example, in lage and the vitreous of the eye. Various muta- (hereditary arthro-opthalmopathy) the only tions in the COL2A1 gene have been found in presenting features at birth may the Pierre- chondrodysplasias with ocular abnormalities Robin association (micrognathia, glossoptosis, (mainly severe myopia), such as spondyloepi- and cleft palate). Mild spondyloepiphyseal physeal dysplasia congenita, Kniest syndrome, dysplasia may develop during childhood as will and Stickler syndrome.9–12 Stickler syndrome is progressive myopia. If untreated, the latter may genetically heterogeneous as families with give rise to and blindness. A mutations in the COL11A2 gene have been careful family history might also give a clue reported.13 These families do not show eye if—for example, other family members had abnormalities because the á2 chain of type XI short stature, flat facies, painful joints, and collagen is replaced by the COL5A2 product in severe myopia with or without retinal detach- mammalian vitreous. These are early days for ment. Mutation analysis of the COL2A1 gene genotype–phenotype correlations. might also confirm the diagnosis, although this Other mutated collagen genes have also been is still a research exercise. associated with skeletal dysplasias, such as the COL10A1 gene in Schmid metaphyseal dys- Molecular genetics plasia and the COL9A2 gene in multiple As a result of developments in molecular epiphyseal dysplasia.14 15 In other families with genetics, several genes and their products multiple epiphyseal dysplasia, mutations in the involved in bone dysplasias have been charac- cartilage oligomeric matrix protein (COMP) terised. This allows the confirmation of clinical gene have been reported,16 which reflects the diagnoses, it broadens knowledge about patho- genetic heterogeneity of this disorder. Muta- genesis, and begins to present an opportunity tions of the COMP gene (deletions or duplica- http://adc.bmj.com/ to develop a rational classification of skeletal tions) also cause 40% of the cases of dysplasias on the basis of the mutated gene(s) pseudoachondroplasia.16 (table 3). For three dysplasias—achondrogenesis IB, Most skeletal dysplasias are dominantly atelosteogenesis II, and diastrophic inherited so parental appearance may assist, dysplasia17—which are all characterised by but the majority arise by de novo mutations micromelia and a short, narrow thorax in vari-

and parents are phenotypically normal. Some ous degrees of severity, mutations in the on September 26, 2021 by guest. Protected copyright. dysplasias are recessively inherited and there diastrophic dysplasia sulphate transporter are major implications for further oVspring of (DTDST) gene have been reported.17 All three the parents. In such cases, reliable prenatal disorders are recessively inherited and there- diagnosis by ultrasound and/or molecular and fore mutation analysis may be very helpful for biochemical analyses of chorionic villi or accurate prenatal diagnosis. amniocytes would be very useful. Mutations in the fibroblast growth factor receptor 3 (FGFR3) gene are involved in Management achondroplasia, thanatophoric dysplasia, and Once a diagnosis has been made, the prognosis hypochondroplasia. The FGFR3 gene, which becomes (reasonably) obvious as do the is expressed in articular chondrocytes, is genetic implications, but there are still many involved in local regulation of cartilage growth. gaps in our knowledge. For example, there are More than 98% of achondroplasia patients no data relating parental heights to childhood have a glycine→arginine substitution at codon outcomes. We are not good at predicting which 380 of the FGFR3 gene.34 In thanatophoric short children with the radiological spinal fea- dysplasia several mutations in the FGFR3 tures of hypochondroplasia, a failure of the gene, either substitutions or missense muta- interpedicular width to increase from L1 to tions, have been reported.56The diVerences in L5—which we regard as the sine qua non of the severity between achondroplasia and thanato- diagnosis—will miss out on the puberty growth phoric dysplasia can be explained by the eVect spurt.18 We hope that correlating genotype to of the mutations on the functioning of the phenotype (a project in progress) may assist in fibroblast growth factor receptor. These muta- oVering a firm prognosis in this most common tions are thought constitutively to activate the of skeletal dysplasias. The genotype of the 288 Brook, de Vries Arch Dis Child: first published as 10.1136/adc.79.3.285 on 1 September 1998. Downloaded from (about double that used for replacement treat- 190 97 90 ment in children). The implication of this must 180 75 be to start r-hGH treatment early before too 50 170 25 much height has been lost (as growth velocity 10 21 3 in the first year of life is normal ), and prelimi- 160 nary analysis of our data in 31 cases suggests 150 that treatment is indeed most eVective when started before the age of 2 years (Ramaswami, 140 Stop growth personnal communication, 1998). 130 hormone There is no prospect that growth hormone Femoral leg alone will achieve anything resembling a 120 cm lengthening normal final height in these patients. It may at 110 Tibial leg most achieve a gain of about 10–15 cm if treat- ment is started early, so it will certainly have to 100 lengthening be coupled with one or more leg lengthening 90 Start growth hormone procedures to obtain a further 10–15 cm. Fig- 80 ure 2 shows the growth chart of our longest treated achondroplastic boy. He received 70 growth hormone from age 7.5 years (late by 60 our standards) and underwent two leg length- ening operations at 11.9 and 14.9 years, result- 50 ing in a final height of 154.6 cm (the mean 132 78645 9 10111213141516171819 (SD) for untreated achondroplastic boys is 131 Age (years) (6) cm).21 Figure 2 Growth chart of achondroplastic patient treated Results of using r-hGH in older achondro- with growth hormone and surgical procedures. plastic children have been rather disappointing in our hands, and compliance with the proband may allow for antenatal diagnosis in therapeutic regimen has been a major problem. future oVspring. It is not known whether r-hGH has a place in Treatment has thus far been confined to limb the management of puberty growth in lengthening. This is a formidable undertaking achondroplasia nor how puberty hormones will as it requires one day of stretching for every impact on an achondroplastic child already on millimetre of length gained in the limb. r-hGH treatment. Although surgical techniques are improving We have very little experience of medical rapidly, problems with soft tissues during treatment in the other skeletal dysplasias and lengthening are common and non-union does no long term results. We have been encouraged sometimes occur. Nevertheless, this is a tried by our experience in multiple epiphyseal and tested procedure, which can add up to dysplasia and Jeune syndrome but discouraged 15 cm in leg length if lengthening is applied to by experience in spondyloepiphyseal dysplasias both tibiae and femora. There are no data, but and pseudachondroplasia. Mean results con- http://adc.bmj.com/ plenty of opinions, available to determine when ceal individual successes and we have seen is the optimal time (medically or psychologi- some unexpected ones; therefore, as we have cally) to operate, whether it is better to operate seen no serious side eVects from medical treat- more than once on a patient, how much ment, we are inclined to advise an empirical lengthening should be attempted, and so on. approach to individual cases. In assessing Medical treatments are in their infancy. results of such trials of n = 1, the problem of

When pituitary derived human growth hor- compliance is one that needs serious discussion on September 26, 2021 by guest. Protected copyright. mone was withdrawn in 1985 and recombinant and consideration. Our recommendation is human growth hormone (r-hGH) became that such trials of treatment should be carried available, clinicians were presented for the first out only in the context of planned research in time with a supply of growth hormone limited an appropriate setting, so that definitive results only by cost. Many indications for the proper can be acquired. use of r-hGH have been explored but data on final heights achieved are only just becoming available and are frankly rather disappointing Conclusions in Turner syndrome, precocious puberty, and Skeletal dysplasias are a common cause of normal short children.19 unexplained short stature in children and There are no data available for final heights adults; they present particularly with a failure achievable in skeletal dysplasias. We have been of pubertal growth. Diagnosis requires a high able to restore a missing pubertal growth spurt degree of clinical suspicion. Collaboration in patients with hypochondroplasia by admin- between an experienced clinician, an informed istering r-hGH at the appropriate time but its radiologist, and a molecular genetic laboratory use earlier in childhood does not look promis- oVers the possibility of a better outcome for ing for significantly improving final height.20 some patientss. The growth of untreated achondroplastic children is well characterised21; we have been The authors are grateful to Dr M Chapman and Dr CM Hall for assistance with radiology in these patients, and to Professor RM greatly encouraged to find that we have been Winter and Dr PC Hindmarsh for helpful comments on the able to keep such patients growing at a 50th manuscript. The studies of genotype–phenotype correlations in achondroplasia and hypochondroplasia are supported by grants centile velocity for normal children by using from Children Nationwide Medical Research Fund and r-hGH at a dosage of 30–40 units/m2/week Pharmacia and Upjohn. Skeletal dysplasias 289 Arch Dis Child: first published as 10.1136/adc.79.3.285 on 1 September 1998. Downloaded from 1 International Working Group on Constitutional Diseases of 11 Winterpacht A, Hilbert M, Schwarze U, Mundlos S, Bone. International classification of osteochondrodyspla- Spranger J, Zabel BU. Kniest and Stickler dysplasia pheno- sias. Am J Med Genet 1992;44:223–9. types caused by collagen type II gene (COL2A1) defect. 2 Oberklaid F, Danks DM, Jensen F, Stace L, Rosshandler S. Nat Genet 1993;3:323–6. Achondroplasia and hypochondroplasia. Comments on 12 Ahmad NN, Ala-Kokko L, Knowlton RG, et al. Stop codon frequency, mutation rate, and radiological features in skull in the procollagen II gene (COL2A1) in a family with the Stickler syndrome (arthro-ophthalmopathy). and spine. 1979; :140–6. Proc Natl J Med Genet 16 Acad Sci USA 1991;88:6624–7. 3 Shiang R, Thompson LM, Zhu Y-Z, et al. Mutations in the 13 Vikkula M, Mariman ECM, Lui VCH, et al. Autosomal transmembrane domain of FGFR3 cause the most dominant and recessive osteochondroplasias associated common genetic form of dwarfism, achondroplasia. Cell with the COL11A2 locus. Cell 1995;80:431–7. 1994;78:335–42. 14 Warman ML, Abbott M, Apte SS, et al. A type X collagen 4 Bellus GA, HeVeron TW, Ortiz de Luna RI, et al. mutation causes Schmid metaphyseal chondrodysplasia. Achondroplasia is defined by recurrent G380R mutations Nat Genet 1993;5:79–82. of FGFR3. Am J Hum Genet 1995;56:368–73. 15 Muragaki Y, Mariman ECM, van Beersum SEC, et al.A 5 Tarvormina PL, Shiang R, Thompson LM, . Thanato- mutation in the gene encoding the alpha2 chain of the et al fibril-associated collagen IX, COL9A2, causes multiple phoric dysplasia (types I and II) caused by distinct epiphyseal dysplasia (EDM2). 1996;12:103–5. mutations in fibroblast growth factor receptor 3. Nat Genet Nat Genet 16 Briggs MD, HoVman SMG, King LM, et al. Pseudoachon- 1995;9:321–8. droplasia and multiple epiphyseal dysplasia due to 6 Rousseau F, Saugier P, Le Merrer M, et al. Stop codon mutations in the cartilage oligomeric matrix protein gene. FGFR-3 mutations in thanatophoric dwarfism type I. Nat Nat Genet 1995;10:330–6. Genet 1995;10:11–12. 17 Hästbacka J, Superti-Furga A, Wilcox WR, Rimoin DL, 7 Naski MC, Wang Q, Xu J, Ornitz DM. Graded activation of Cohn DH, Lander ES. Atelosteogenesis type II is caused by fibroblast growth factor receptor 3 by mutations causing mutations in the diastrophic dysplasia sulphate-transporter achondroplasia and thanatophoric dysplasia. Nat Genet gene (DTDST): evidence for a phenotypic series involving 1996;13:233–7. three chondrodysplasias. Am J Hum Genet 1996;58:255–62. 8 Bellus GA, McIntosh I, Smith EA, et al. A recurrent muta- 18 Appan S, Laurent S, Chapman M, Hindmarsh PC, Brook tion in the tyrosine kinase domain of fibroblast growth fac- CGD. Growth and growth hormone therapy in hypochon- tor receptor 3 causes hypochondroplasia. droplasia. Acta Paediatr Scand 1990;79:796–803 Nat Genet 19 Donaldson MDC. Jury still out on growth hormone for nor- 1995;10:357–9. mal short stature and Turner’s syndrome. Lancet 1996;348: 9 Lee B, Vissing H, Ramirez F, Rogers D, Rimoin D. Identifi- 3–4. cation of the molecular defect in a family with spondyloepi- 20 Hindmarsh PC, Bridges NA, Brook CGD. Wider indica- physeal dysplasia. Science 1989;244:978–80. tions for treatment with biosynthetic human growth 10 Tiller GE, Rimoin DL, Murray LW, Cohn DH. Tandem hormone in children. Clin Endocrinol 1991;34:417–28. duplication within a type II collagen gene (COL2A1) exon 21 Horton WA, Rotter JI, Rimvion DL, Scott CJ, Hall JG. in an individual with spondyloepiphyseal dysplasia. Proc Standard growth curves for achondroplasia. J Paediatr Natl Acad Sci USA 1990;87:3889–93. 1978; 93:435–8.

FETAL AND NEONATAL EDITION September Issue

The following articles—being published in the September issue of the Fetal and Neonatal edition of Archives of Disease in Childhood—may be of particular general interest as they relate to community, social, and neurodevelopmental paediatrics. http://adc.bmj.com/ Outcome of very preterm birth: children reviewed with ease at 2 years diVer from those followed up with diYculty Win Tin, Susan Fritz, Unni Wariyar, Edmund Hey Maternal hypertension and neurodevelopmental outcome in very preterm infants Peter H Gray, Michael J O’Callaghan, Heather A Mohay, Yvonne R Burns, James F King

Neurobehaviour of school age children born to diabetic mothers on September 26, 2021 by guest. Protected copyright. A Ornoy, N Ratzon, C Greenbaum, E Peretz, D Soriano, M Dulitzky Association of blood pressure in adolescence with birthweight P O D Pharoah, C J Stevenson, C R West Birthweight and blood pressure among children in Harare, Zimbabwe Godfrey Woelk,Irvin Emanuel, Noel S Weiss, Bruce M Psaty Causes of preterm delivery and intrauterine growth retardation in a malaria endemic region of Papua New Guinea S J Allen, A Raiko, A O’Donnell, N D E Alexander, J B Clegg Histochemical, clinical, and in vitro â cell responses in a neonate with persistent hyperinsulinaemic hypoglycaemia of infancy N S Panesar, C W Poon, C T Liew, G W K Wong, N M Hjelm